Genetic and environmental risk factors for diabetes and vascular complications of diabetes have been studied in the Pima Indians. The residents of the study area, currently numbering approximately 5000 people, have participated in a longitudinal population study for the last 21 years, allowing observations of the natural history of diabetes mellitus and its complications. Nondiabetic subjects with impaired glucose tolerance (IGT) are at high risk of deteriorating to diabetes (27% in 5 years and 48% in 10 years). Decompensation from IGT to diabetes was most likely in those with high fasting insulin concentrations (suggesting insulin resistance) and low two-hour insulin responses to an oral glucose challenge (suggesting impaired insulin responsiveness), consistent with the hypothesis that there are two defects contributing to the development of diabetes: insulin resistance and impaired insulin secretion. Other risk factors for diabetes include obesity, and it was determined from long-term followup of nondiabetic subjects that those with obesity of long duration have a greater incidence of diabetes than the recently obese who have had rapid weight gain. Risk factors for end stage renal disease were investigated in diabetic Pima Indians. Fasting plasma glucose concentration, duration of insulin use, higher blood pressure, the number of urinary tract infections, prescription of aspirin or indomethicin, and ethanol abuse were predictive factors for this lethal complication of diabetes.